The present invention relates to novel compounds for use as imaging agents. In particular, the present invention relates to paramagnetic metal clusters with oxygen and/or nitrogen containing ligands useful as contrast agents for magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and magnetic resonance spectroscopy imaging (MRSI).
The phenomenon of NMR was discovered in 1945, but only recently has found application for enhancing images of internal body structures, such as organs and tissues. The technique of MRI involves the detection of certain atomic nuclei; i.e. those possessing magnetic dipole moments, utilizing magnetic fields and radio-frequency radiation.
The images produced by MRI provide a cross-sectional display of body anatomy and give excellent resolution of soft tissue detail. The images are usually produced by mapping a distribution of protons and their relaxation times in the organs or tissues. Because there is a lack of any known hazard associated with the level of the magnetic and radio-frequency fields that are employed using MRI techniques, repeated scans of individuals can be performed without risk. MRI techniques are also advantageous as they are non-invasive, avoiding the use of ionizing radiation. Additionally, MRI techniques allow for any scan plane to be readily selected, including transverse, coronal, and sagittal sections.
It is believed that MRI has a greater potential for selective examination of tissue characteristics than other known techniques, such as X-ray computed tomography (CT). This is because the known techniques rely on a limited number of coefficients to determine image contrast, such as X-ray attenuation and coefficients for CT, while the MRI signal relies on at least four variable; T1, T2, proton density, and flow. Also, MRI is more sensitive to subtle physicochemical differences between organs and tissues, and it is therefore believed that MRI may be capable of differentiating different tissue types and detecting diseases which induce physicochemical changes that may not be detected by other known techniques, such as CT which is only sensitive to differences in the electron density of tissue.
The hydrogen atom, which has a nucleus consisting of a single unpaired proton, has the strongest magnetic dipole moment of any nucleus. Hydrogen is abundant in the human body, occurring in both water and lipids. Therefore, MRI techniques are most commonly used to produce images based upon the distribution density of hydrogen atoms and the relaxation times of the hydrogen atoms in organs and tissues. However, there are other nuclei which also exhibit a nuclear magnetic resonance phenomenon, such as carbon-13 (six protons, seven neutrons), fluorine-19 (nine protons and ten neutrons), sodium-23 (eleven protons and twelve neutrons), and phosphorus-31 (fifteen protons and sixteen neutrons).
MRI techniques are carried out by irradiation of the desired body area with pulsed radio-frequency (RF) energy in a controlled gradient magnetic field. The nuclei or protons within the applied magnetic field tend to align in the direction of the magnetic field. However, when irradiated with the RF energy pulse, the nuclei or protons are "excited" and their spin is altered. This causes an effective tipping of the nuclei or protons out of the magnetic field direction; the extent of tipping is dependent on the pulse duration and energy. Following the application of the RF pulse, the nuclei or protons "relax" or return to equilibrium and realign with the magnetic field, emitting radiation at the resonant frequency of the nuclei or proton in the process.
The decay of the emitted radiation is characterized by two relaxation times, T1 and T2. T1 is the spin-lattice relaxation time or longitudinal relaxation time, i.e., the time taken by the nuclei or protons to return to equilibrium along the direction of the applied magnetic field. T2 is the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins. Relaxation times have been established for various fluids, organs and tissues in different species of mammals.
The relaxation times, T1 and T2 are essentially mechanisms whereby the energy imparted by the RF pulse is subsequently dissipated to the surrounding environment. Therefore, these relaxation times are influenced by the environment of the nuclei, such as viscosity, temperature and the like. In addition, the rate of relaxation may be influenced by other molecules or nuclei which are paramagnetic. Therefore, chemical compounds incorporating paramagnetic molecules or nuclei may substantially alter the T1 and T2 values of nearby nuclei having a magnetic dipole moment. The extent of the paramagnetic effect of the given chemical compound is a function of the environment within which it exists. The ability of MRI to detect these paramagnetic influences is one reason for the higher potential of MRI as compared to other techniques, such as CT, as noted above.
An important aspect of MRI is that as the initial spin number of the contrast agent is increased, the T1 and T2 values may be increased, resulting in superior image quality. Therefore, it is desirable to maximize the spin number of the contrast agent while maintaining other necessary qualities thereof, such as overall neutrality of the agent.
In light of the above, MRI agents having a high spin number, which lead to sharp, clear images, would represent a significant advance in the art.